PI: Hugo R. Rosen, MD/ Denver VA Title of Merit Review Grant: Functional attributes of CD8+ T cells in recovery of hepatitis C virus infection Approximately 200 million throughout the world have chronic HCV infection. HCV persists in up to 80% of people infected. In the US alone, the burden over the next 10- 20 years is expected to reach over $10 billion in direct medical costs and double this in overall societal costs. HCV is a leading etiology of liver cancer and cause for liver transplantation. Although new therapies have improved the rates of sustained response, a large proportion of patients (~50%) fail to respond to antiviral treatment or develop significant drug toxicity, thus remaining at risk for disease progression. An understanding of HCV-host interactions is required to combat this virus and to develop improved therapies. Although data derived from the earliest stages of infection provide the greatest mechanistic insights, acute HCV is often unrecognized because symptoms are usually mild or absent. Detailed prospective studies of acute and evolving HCV infection are required to delineate the role of escape mutations in HCV persistence, as well as to define the immunological and virological factors governing viral evolution. In particular, careful dissection of these factors will be critical to the design of any effective T-cell based therapy.